Aryl hydrocarbon receptor activators

Abstract

Small molecule AhR ligands are disclosed. The ligands can induce the differentiation of Tr1 cells to suppress pathogenic immune responses without inducing nonspecific immune suppression. Methods of treatment of autoimmune diseases using the AhR ligands are also disclosed.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows: 
     
         1 . A compound of the formula: 
       
         
           
           
               
               
           
         
         or a tautomer thereof, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, wherein: 
         Q 1  is an optionally substituted C6-C10 aryl; optionally substituted C5-C10 heteroaryl; optionally substituted C5-C10 heterocyclyl; optionally substituted C1-C10 alkyl, or optionally substituted C3-C10 cycloalkyl; 
         Z is C; 
         R 1  is H or halogen; 
         R 2 , R 3 , and R 4  are independently H, halogen, CN, optionally substituted C1-C10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C1-C6 alkoxy, SO 2 R 5 , CO 2 R 5 , or CONR 5 R 6 , or any one of R 1  and R 2 , R 2  and R 3 , and R 3  and R 4  pairs, together with the carbon atoms to which they are attached, forms an optionally substituted a five- or six-membered cycloalkenyl, heterocyclenyl, aryl or heteroaryl; 
         R 5  and R 6  are independently H, optionally substituted C1-C10 alkyl, or optionally substituted C3-C10 cycloalkyl, or R 5  and R 6 , together with the nitrogen atom to which they are attached, form an optionally substituted 5-membered ring or an optionally substituted 6-membered ring; 
         R 7 , at each occurrence, is independently H, halogen, CN, optionally substituted C1-C10 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C1-C10 heteroalkyl, optionally substituted C1-C10 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C5-C10 heteroaryl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 cycloalkyloxy, OCF 3 , NR 5 R 6 , SCF 3 , or C(O)NR 5 R 6 ; and 
         m is an integer from 1 to 7. 
       
     
     
         2 . The compound of  claim 1 , wherein Q 1  is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted optionally substituted C3-C6 cycloalkyl or an optionally substituted quinolinyl. 
     
     
         3 . The compound of  claim 2 , wherein Q 1  is a phenyl optionally substituted with one, two, or three substituents independently selected from F, Cl, Br, OCH 3 , CN, OCF 3 , SCF 3 , t-Bu, NMe 2 , CONH 2 , piperazyl, piperidyl, OCH 2 CH 2 OH, OCH 2 CH 2 NMe 2 , and 1-naphthyl. 
     
     
         4 . The compound of  claim 1 , wherein R 4  is H or halogen. 
     
     
         5 . The compound of  claim 1 , wherein all R 7  are H. 
     
     
         6 . A compound of the formula: 
       
         
           
           
               
               
           
         
         or a tautomer thereof, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, 
         wherein R 2  and R 3 , independently, F, Cl, Br, O(C1-C5 alkyl), SCF 3 , OCF 3 , CO 2 H, CO 2 (C1-C5 alkyl), or CONR 5 R 6 , wherein R 5  and R 6  are independently H, optionally substituted C1-C10 alkyl, optionally substituted C3-C10 cycloalkyl, or R 5  and R 6 , together with the nitrogen atom to which they are attached, form an optionally substituted morpholinyl; and 
         Q 1  is an optionally substituted C6-C10 aryl; optionally substituted C5-C10 heteroaryl; optionally substituted C5-C10 heterocyclyl; optionally substituted C1-C10 alkyl, or optionally substituted C3-C10 cycloalkyl; Z is C. 
       
     
     
         7 . The compound of  claim 6 , wherein Q 1  is a phenyl, cyclopropyl, naphthyl, benzodioxanyl, or quinolinyl, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of F, Cl, Br, CF 3 , SCF 3 , CN, and OCH 3 . 
     
     
         8 . The compound of  claim 1 , or a tautomer thereof, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         9 . A pharmaceutical composition comprising a compound of  claim 1 , or a hydrate thereof, or a pharmaceutically acceptable salt thereof. 
     
     
         10 . A pharmaceutical composition comprising a compound of  claim 6 , or a hydrate thereof, or a pharmaceutically acceptable salt thereof.